Approximately 40 million people in the US suffer from alcohol addiction exhibiting symptoms of uncontrolled alcohol drinking, alcohol tolerance and dependence. The degree of human suffering and economic loss both underscore the need for rational and effective treatments for this disorder. While the rate of alcohol abuse is about 8-10% in the general population, this rate is reported to be 60-80% among Vietnam veterans that suffer from post-traumatic stress disorder (PTSD). PTSD could also arise from severe automobile accidents, physical abuse, or childhood abuse. The PTSD sufferers exhibit symptoms that include recurrence of traumatic stressors, reliving the traumatic experience(s), developing avoidance and numbing (psychosocial isolation), as well as enhancing arousal and anxiety. Alcohol (ethanol) has often been used as a convenient over the- counter medication for temporary relief of PTSD symptoms. However, if tolerance to anti-anxiety (anxiolytic) effects of alcohol develops, the amount of alcohol required for the relief of PTSD symptoms may rise, contributing to the development of alcohol addiction as well as organ damages associate with alcohol abuse. The ability to learn and respond appropriately to external fear is a behavior that is well conserved in mammals, and there is a fear neuronal circuitry which consists of the anterior cingulate cortex (ACC), amygdala, hippocampus, and locus coeruleus. The ACC, in particular, performs a role in assessing the external stimuli and in planning an appropriate response to these stimuli. Recent evidence suggests that the glutamatergic transmission of the ACC is critical for fear learning and also for learned fear responding, and malfunctions of the ACC neurons would heighten external fear stimuli and exaggerate internal fear stimuli leading to high anxiety symptoms. We show that acute moderate concentrations of ethanol can inhibit glutamatergic transmission in the ACC, and that these neurons readily develop acute functional tolerance during ethanol exposure. We hypothesize that ethanol inhibition of glutamatergic transmission of the ACC neurons mediates in part the anxiolytic effects of alcohol, and that tolerance to these effects of alcohol is developed at the ACC neurons by the NR2B NMDA receptor-mediated mechanisms. In the present proposal, we aim to elucidate molecular mechanisms that mediate alcohol tolerance in the ACC neurons. If our hypotheses are proven correct, the drugs targeting NR2B subunit of the NMDA receptor may be useful in treating alcohol addiction. PUBLIC HEALTH RELEVANCE: Acute ethanol tolerance describes a condition where ethanol's effects are reduced during an episode of ethanol binge drinking. This tolerance is believed to be due to adaptive responses of the brain to ethanol. I discovered that excitatory neurotransmitter receptors - NMDA receptors can become tolerant to ethanol and this tolerance may be a result of ethanol-induced neuronal damage. I propose to test whether NMDAR tolerance also occurs in two experimental models of excitotoxic neuronal damage and also to test three new neuroprotective drugs to prevent ethanol tolerance. If the experiments are successful, we could have new medications for treating alcohol addiction.